A Real-world Toxicity Atlas Shows that Adverse Events of Combination Therapies Commonly Result in Additive Interactions

Asli Küçükosmanoglu, Silvia Scoarta, Megan Houweling, Nicoleta Spinu, Thomas Wijnands, Niek Geerdink, Carolien Meskers, Georgi K Kanev, Bert Kiewiet, Mathilde Kouwenhoven, David Noske, Tom Wurdinger, Marianne Pouwer, Mark Wolff, Bart A Westerman

Research output: Contribution to journalArticleAcademicpeer-review


Purpose: Combination therapies are a promising approach for improving cancer treatment, but it is challenging to predict their resulting adverse events in a real-world setting. Experimental Design: We provide here a proof-of-concept study using 15 million patient records from the FDA Adverse Event Reporting System (FAERS). Complex adverse event frequencies of drugs or their combinations were visualized as heat maps onto a two-dimensional grid. Adverse event frequencies were shown as colors to assess the ratio between individual and combined drug effects. To capture these patterns, we trained a convolutional neural network (CNN) autoencoder using 7,300 single-drug heat maps. In addition, statistical synergy analyses were performed on the basis of BLISS independence or x 2 testing. Results: The trained CNN model was able to decode patterns, showing that adverse events occur in global rather than isolated and unique patterns. Patterns were not likely to be attributed to disease symptoms given their relatively limited contribution to drug-associated adverse events. Pattern recognition was validated using trial data from ClinicalTrials.gov and drug combination data. We examined the adverse event interactions of 140 drug combinations known to be avoided in the clinic and found that near all of them showed additive rather than synergistic interactions, also when assessed statistically. Conclusions: Our study provides a framework for analyzing adverse events and suggests that adverse drug interactions commonly result in additive effects with a high level of overlap of adverse event patterns. These real-world insights may advance the implementation of new combination therapies in clinical practice.

Original languageEnglish
Pages (from-to)1685-1695
Number of pages11
JournalClinical cancer research : an official journal of the American Association for Cancer Research
Issue number8
Publication statusPublished - 15 Apr 2024


  • Drug Interactions
  • Drug-Related Side Effects and Adverse Reactions/diagnosis
  • Humans

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